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BOSTON—Biopharmaceutical company Zafgen Inc. in April announced new data from its bestPWS ZAF-311 study—a pivotal, double-blind, placebo-controlled Phase 3 trial evaluating the safety and efficacy of the company’s lead product candidate beloranib—in patients with Prader-Willi syndrome (PWS) during the six-month randomized treatment period. Beloranib, a MetAP2 inhibitor, is a novel, first-in-class, twice-weekly subcutaneous injection being developed for the treatment of multiple indications, including severe obesity in PWS; obesity caused by hypothalamic injury, including craniopharyngioma-associated obesity; and severe obesity in the general population.
In the bestPWS ZAF-311 study, patients received twice-weekly subcutaneous injections of either 2.4 mg or 1.8 mg of beloranib or placebo. The trial included patients whose average age was 20 years. Patients in the trial were markedly obese at baseline; at the beginning of randomized treatment, patients had an average BMI of 40 kg/m2, an average body weight of 100 kg, an average fat mass of 51 kg and an average hyperphagia total score of 16.9 (consistent with moderate to severe hyperphagia).
Of the 107 patients in the study, 74 completed the full 26 -week treatment per the study protocol, and 27 patients completed at least 75 percent of the treatment period prior to the suspension of dosing in the trial in October 2015.
The trial had two primary efficacy endpoints: improvement in hyperphagia-related behaviors and reduction in body weight. Patients treated with both the 1.8 mg and 2.4 mg doses of beloranib demonstrated a significant reduction in total body mass and fat mass, with approximately 90 percent of the total body mass lost being from body fat reduction, indicating preferential loss of fat rather than lean mass.
The control group of patients receiving placebo experienced a substantial (4.15 percent) increase in body weight over the six-month course of randomized treatment, which is expected in this patient population that typically experiences weight gain throughout life without effective treatment for managing obesity. By contrast, patients treated with beloranib experienced a reduction in weight as high as a 5.3-percent reduction from baseline in the group treated with the larger (2.4 mg beoranib) dosage, with a placebo-adjusted weight loss of 9.45 percent.
Secondary endpoints in the study included improvement in total body fat mass and improvement in lipids and markers of cardiometabolic risk (TC and LDL). The results showed beloranib to be associated with improvements in total and LDL cholesterol and with the other markers of cardiometabolic risk, compared to placebo, while the mean change in HDL cholesterol and triglycerides showed no significant change from baseline for each treatment group. The reduction in leptin levels and increase in adiponectin levels observed in patients at both beloranib dosages in the study are consistent with altered fatty acid mobilization and lipid utilization.
At the end of the randomized treatment period, there were no clinically significant abnormal patterns regarding laboratory values, vital signs or electrocardiography findings. Six patients in the study, however, withdrew due to adverse effects; a total of five serious adverse events were reported during the trial. The most common adverse events encountered during the study were injection site bruising, aggression and hyperphagia; these occurrences were generally mild and temporary. Of these, only injection site bruising was reported notably more frequently in patients taking beloranib compared to placebo.
Serious adverse events that occurred during the study include aggression (placebo, 2.4 mg beloranib), ankle fracture (placebo), mental status change (1.8 mg beloranib) and pulmonary embolism (1.8 mg beloranib). The study’s authors note, however, that many of these—specifically psychiatric disorders—are commonly observed as background comorbidities in PWS patients.
Zafgen has previously disclosed an association of venous thromboembolic events reported in patients treated with beloranib vs. placebo, including one fatal case of pulmonary embolism (1.8 mg beloranib) during the randomized portion of the bestPWS study that was reported in October 2015. No other venous thromboembolic events were reported during the blinded randomized portion of the bestPWS study. Also previously reported was a second patient death associated with pulmonary embolism (2.4 mg beloranib) and two cases of deep vein thrombosis (1.8 mg and 2.4 mg beloranib), which occurred during the open-label extension portion of the bestPWS study; no other deaths have occurred over the course of the beloranib program.
“The ZAF-311 study demonstrated that beloranib has a clear efficacy benefit in PWS patients,” says Dr. Thomas Hughes, CEO of Zafgen. “We are actively working to better understand the mechanisms and incidence of underlying thromboembolic disease in PWS, as well as the potential impact of beloranib treatment on thrombosis in order to better understand the benefit/risk relationship of beloranib and develop a strategy for risk mitigation in this high-risk patient population.”
In an effort to resolve the full clinical hold the FDA placed on the beloranib IND in December 2015, Zafgen plans to present the data from the ZAF-311 clinical trial, along with previously reported data from the ZAF-203 Phase 2b clinical trial of beloranib in obesity complicated by type 2 diabetes, as well as a proposal for a risk-mitigation strategy for beloranib in PWS.
“We look forward to identifying a path forward for beloranib in PWS and providing an update from our discussions with the FDA,” says Hughes.
In other recent PWS news unrelated to Zafgen, Lyon, France-based Alizé Pharma SAS, an Alizé Pharma group company specialized in the development of biopharmaceuticals to treat metabolic disorders and rare diseases, announced top-line results of a Phase 2 clinical trial of AZP-531, its unacylated ghrelin analog, in patients with PWS.
This randomized, double-blind, placebo-controlled, European multicenter study was aimed at evaluating the safety, tolerability and efficacy of AZP-531 administered daily subcutaneously for 14 days on food-related behavior vs. placebo. The trial was conducted across seven centers in France, Spain and Italy. It enrolled a total of 47 patients with genetically diagnosed PWS and evidence of hyperphagia.
The results showed a significant improvement in food-related behavior in patients treated with AZP- 531, as assessed by the Hyperphagia Questionnaire (HQ), the most widely used tool for assessing efficacy in clinical trials in PWS. The results showed a particular improvement in the Hyperphagic Severity domain score of the HQ. These findings were supported by a reduction in appetite following breakfast for patients treated with AZP-531, as assessed by a newly developed patient-reported outcome scale.
Glucose control improved with AZP-531 treatment, with a greater effect observed in patients with higher fasting or postprandial glucose levels at baseline. Body weight did not change significantly in either group, which is not unexpected following short-term treatment in a study population with a highly variable weight. However, a significant reduction in waist circumference was noted in the AZP-531 group, which was not observed in the placebo group.
AZP-531 was well tolerated with no serious or severe adverse events and no clinically significant changes with respect to safety laboratory tests.
“Hyperphagia is a devastating feature of Prader-Willi Syndrome as it dramatically impairs the quality of life of the patients and their families and may also lead to morbid obesity and related cardiovascular complications. In this regard, the impact of AZP-531 on food- related behavior in this trial is clinically relevant, highly promising and calls for the implementation of longer-term clinical trials,” said Prof Maïthé Tauber, a pediatric endocrinologist at the Hospital of Toulouse, coordinator of the Reference Center for Prader-Willi Syndrome in France and the coordinating principal investigator of the study.